We described insulin glargine (originator) and insulin glargine-yfgn (biosimilar) treatment patterns, assessed effectiveness and safety outcomes, and identified reasons for switching back to the originator product from the biosimilar. This retrospective study included 328,463 Veterans 18 years of age and older who received one or more outpatient prescriptions for insulin glargine and/or insulin glargine-yfgn between 1 June 2021 and 31 December 2022. Patients were assigned to subgroups based on the initial prescription during the study period, prevalent versus incident use for originator insulin glargine, and prior versus no prior use of the originator before the biosimilar (i.e., prevalent originator non-switcher (n = 189,734), originator switch to biosimilar (n = 81,010), incident originator non-switcher (n = 49,401), and incident biosimilar (n = 8318)). There were no differences in the outcome of mean HbA1c (7.9% for all subgroups). There were also no differences in the unadjusted rates of hospitalization and/or emergency room visits for hyper- and hypoglycemia between the prevalent originator non-switcher and originator switched to biosimilar subgroups (p = 0.09 and 0.38, respectively) or the incident originator non-switcher and incident biosimilar subgroups (p = 0.054 and 0.61, respectively). Finally, none of the HbA1c or hyperglycemia outcomes adjusted for baseline characteristics were statistically different. Adjusted analyses for rates of hospitalization and/or emergency room visits for hypoglycemia could not be performed due to the low number of events. Overall, patients who received insulin glargine-yfgn had similar effectiveness and safety outcomes as patients who received the originator. Full article

Introduction: Calcineurin inhibitors (CNIs), ciclosporin and tacrolimus, are utilized primarily in organ transplantation and the treatment of autoimmune diseases. Since patients depend on these drugs over long periods, they face a potential risk of intoxication. This risk increases substantially when patients are overdosed or inadvertently exposed to cytochrome P450 (CYP) 3A4 inhibitors. Objectives: To analyze the utility of CYP inducers as a plausible treatment modality for acute CNI intoxication using real-world data from the WHO global pharmacovigilance database (VigiBase™) and supporting evidence from published data. Methodology: We explored all individual case safety reports (ICSRs) regarding CNI intoxications registered in VigiBase™. The queries “overdose” or “drug intoxication” were applied against the active ingredients “ciclosporin” and “tacrolimus”. Regarding the utility of CYP inducers, an extensive literature analysis was undertaken. We also report an index clinical case of a 60-year-old liver transplant patient that developed severe tacrolimus intoxication with multiple organ dysfunction at a peak concentration of 33.1 μg/L after a single dose of intravenous fluconazole. Results: Out of 143,710 documented ICSRs reported in VigiBase™ since 1992, 0.26% and 0.02% were registered as CNI overdoses and intoxications, respectively. The main etiological factor for CNI intoxication was the interaction with CYP 3A4 inhibitors (40.0% vs. case reports: 50.0%). The most commonly reported manifestation was acute kidney injury (36.7% vs. case reports: 46.3%). A total of 16.7% of intoxications led to fatal outcomes after drug withdrawal or dose reduction; however, in 43.0% of cases the exact actions undertaken were not reported. In peer-reviewed reports, 34 distinct clinical cases were treated with CYP inducers. Diverse pharmacoenhancement strategies with phenobarbital (5), phenytoin (23) and rifampicin (6) were described with a mean time of achieving the therapeutic target after 2.7 (±0.7), 3.1 (±0.5) and 4.6 (±1.0) days, respectively. In the index case, a therapeutic concentration of 4.9 [4–6 μg/L] was achieved after a 3-day regimen of rifampicin. Conclusion: In addition to general supportive treatment, the administration of phenobarbital, phenytoin, or rifampicin to reverse acute CNI intoxication is a viable treatment modality. The relatively long half-life of phenobarbital coupled with its exclusive renal elimination are potential pitfalls to reckon with. In spite of the favorable pharmacokinetic advantages of rifampicin, phenytoin offers a competitive pharmacodynamic advantage that is indisputable in patients with overt neurotoxicity. Full article

Though it is well documented that antidepressants are associated with an increased risk of falls in older adults at the drug class level, the comparative risk between individual antidepressants for fall injury in older adults with depression is unknown. Currently, clinicians are making decisions at the drug class level without consideration of the potential that there could be safer choices within classes. We compared the risk of fall injury among initiators of bupropion, duloxetine, fluoxetine, paroxetine, and venlafaxine to those of (es)citalopram and, separately, sertraline. We performed a retrospective cohort study using the MarketScan^® Medicare Supplemental claims from 2007 to 2019. Individuals had incident depression (washout in previous continually enrolled year) with a first antidepressant claim up to three months after depression diagnosis. Individuals were followed for the first three months of antidepressant use until the first occurrence of fall injury, change/discontinuation of antidepressant, discontinued insurance coverage, or end of study. Propensity score inverse probability of treatment-weighted Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals for each antidepressant comparison and fall injury. We identified 114,505 individuals (mean age 76.6 years, 68% female, 97% without prior fall). A higher risk of fall injury was associated with initiating bupropion (HR 1.20 to 1.61), duloxetine (HR 1.27 to 1.36), paroxetine (HR 1.14 to 1.22), and venlafaxine (HR 1.22 to 1.34) when compared to (es)citalopram or sertraline. New use of duloxetine, bupropion, paroxetine, and venlafaxine was associated with a higher risk of fall injury compared to (es)citalopram and sertraline. Full article

COVID-19 pandemic-related pressures on primary care may have driven the inappropriate continuation of antibiotic prescriptions. Yet, prescribing modality (repeat/non-repeat) has not previously been investigated in a pandemic context. With the approval of NHS England, we conducted a retrospective cohort study of >19 million English primary care patient records using the OpenSAFELY-TPP analytics platform. We analysed repeat/non-repeat prescribing frequency in monthly patient cohorts between January 2020 and 2022. In-depth analysis was conducted on January 2020 (“pre-pandemic”) and January 2021 (“pandemic”) cohorts (with a particular focus on repeat prescribing). Per-patient prescribing and clinical conditions were determined by searching primary care records using clinical codelists. Prescriptions in a 6-month lookback period were used to delineate repeat prescribing (≥3 prescriptions) and non-repeat prescribing (1–2 prescriptions). Associations between demographics (e.g., age, sex, ethnicity) and prescribing were explored using unadjusted risk ratios. The frequency of clinical conditions among prescribed patients was examined. Antibiotic prescribing declined from May 2020; non-repeat prescribing declined more strongly than repeat prescribing (maximum declines −26% vs. −11%, respectively). Older patients were at a higher risk of prescribing (especially repeat prescribing). Comorbidities were more common among repeat- vs. non-repeat-prescribed patients. In the pandemic cohort, the most common clinical conditions linked to repeat prescribing were COPD comorbidity and urinary tract infection. Our findings inform the ongoing development of stewardship interventions in England, targeting patient groups wherein there is a high prevalence of repeat prescribing. Full article

Background: The extensive use of antibiotics has contributed to the development of antibiotic resistance. Understanding the factors behind the attitude of physicians in prescribing antibiotics may be useful to address educational interventions to sensitize them to a more rational use of these drugs. This study aimed to evaluate the general practitioners’ (GPs) characteristics potentially associated with antibiotic prescription in community-dwelling adults from 2000 to 2019. Method: Multivariable linear regression models were performed to evaluate the association of GPs’ characteristics with the mean number of different antibiotics prescribed and the mean number of Defined Daily Doses (DDD) prescribed per patient. Results: We found that GPs older than 60 years prescribed a smaller number of different antibiotics per patient compared to 30–40 years old GPs (mean (standard error) 1.4 (0.5) vs. 1.8 (0.4)). In contrast older GPs prescribed more DDD compared to younger ones (28.9 (0.1) vs. 27.3 (0.3)). GPs prescribed 29 (0.1) DDD for >200 patients on polypharmacy vs. 28 (0.1) DDD for <100 patients on polypharmacy. The mean number of DDD prescribed increased by 5 units and by 16 units for each refill and switch, respectively. Conclusions: Age and number of patients in polypharmacy in charge were found to be associated with higher antibiotic prescriptions. The knowledge of the GPs-related factors could allow the stakeholders to design interventions to sensitize them to a more appropriate use of antibiotics in view of the increasing issue of antibiotic resistance. Full article

We examined eligibility criteria from recent oncology clinical trials to see whether real-world data (RWD) from electronic health records (EHRs) could be used to create external control groups for clinical trials. Trials were identified from the Aggregate Analysis of ClinicalTrials.gov database; the selected trials were for oncology drugs approved by the FDA in 2020. Verbatim text from trial inclusion and exclusion criteria was qualitatively assessed by an expert panel to determine if criteria could be ascertained from structured and unstructured EHR data. Identified criteria were categorized (cancer-related, comorbidity-related, demographic, functional status, and trial operations) and subcategorized. Among 53 identified trials, 20 met the requirements for study inclusion, which included 463 eligibility criteria. Percentages of criteria by category were as follows: cancer-related factors (46%), comorbidities (20%), functional status (18%), trial operations (14%), and demographics (2%). For 18 of the 20 trials, 80% of the eligibility criteria could be ascertained with RWD; for 4 of the 20, it was 100%. When trial operation-specific criteria were excluded, all 20 met the 100% threshold. Our study indicates that both structured and unstructured data from community-based oncology-specific EHRs can be used for determining patient eligibility for external control arms for clinical trials. Full article

Irrational and inappropriate prescribing of antibiotics is a major problem that can lead to the development of antimicrobial resistance (AMR). In Zambia, there is insufficient information on the prescribing patterns of antibiotics according to the World Health Organization (WHO) AWaRe classification. Therefore, this study assessed the prescribing patterns of antibiotics using the AWaRe classification during the COVID-19 pandemic at the University Teaching Hospital in Lusaka, Zambia. A cross-sectional study was conducted using 384 patient medical files at the University Teaching Hospital in Lusaka, Zambia, from August 2022 to September 2022. All antibiotics were classified according to the WHO “AWaRe” tool and assessed for appropriateness using the 2020 Zambian Standard Treatment Guidelines. Of the 384 patient medical files reviewed, antibiotics were prescribed 443 times. The most prescribed antibiotics were ceftriaxone (26.6%), metronidazole (22.6%), amoxicillin (10.4%), amoxicillin/clavulanic acid (5.6%), and azithromycin (5%). The prescribing of 42.1% of “Watch” group antibiotics was greater than the recommended threshold by the WHO. Most antibiotics were prescribed for respiratory infections (26.3%) and gastrointestinal tract infections (16.4%). The most prescribed antibiotic was ceftriaxone, a Watch antibiotic. This is a worrisome observation and calls for strengthened antimicrobial stewardship and implementation of the AWaRe framework in prescribing antibiotics. Full article

Although 5-Aminosalicylate (5-ASA) has been shown to act on the local mucosa, when 5-ASA is orally administered, most of it is absorbed in the upper gastrointestinal tract and does not reach the large intestine, where lesions are present. Therefore, different drug delivery systems have been developed for each oral 5-ASA formulation. Currently, the oral 5-ASA formulation approved in Japan is salazosulfapyridine (SALAZOPYRIN^®; Pfizer Japan Inc.: Tokyo, Japan), in which 5-ASA and sulfapyridine are azo-bonded. In addition, there are several 5-ASA release formulations, including ASACOL^®; ZERIA Pharmaceutical Co., Ltd.: Tokyo, Japan (delayed release formulation dependent on pH), PENTASA^®; KYORIN Pharmaceutical Co., Ltd.: Tokyo, Japan (delayed release formulation dependent on time), and LIALDA^®; MOCHIDA Pharmaceutical Co., Ltd.: Tokyo, Japan (delayed release formulation dependent on pH and time). Adverse events may occur because of differences in the drug delivery systems of these products. In this study, we focused on the adverse events of different 5-ASA formulations and investigated differences in the detection of safety signals for each 5-ASA formulation using disproportionality analysis. There were 15 adverse events detected only with SALAZOPYRIN^®. On the other hand, ASACOL^®, PENTASA^®, and LIALDA^® have different drug delivery systems. Although the detected signal intensities varied, the detected adverse events were not significantly different. These findings provide important insights, which should be considered by physicians during treatment selection and drug manufacturers during drug development. Full article

Helicobacter pylori is a class I carcinogen that infects more than 100 million individuals in the United States. Antimicrobial therapy for H. pylori has typically been prescribed empirically rather than based on susceptibility testing. Until recently, therapeutic recommendations have generally ignored the principles of antibiotic stewardship. A combination of a proton pump inhibitor (PPI), amoxicillin, and clarithromycin (triple therapy) remains popular despite increasing clarithromycin resistance and poor cure rates. Concomitant therapy (a PPI, amoxicillin, clarithromycin, and metronidazole) is recommended and widely used despite all patients receiving at least one unneeded antibiotic. In 2020, the Food and Drug Administration approved vonoprazan, amoxicillin, and clarithromycin triple therapy, which administers unneeded clarithromycin to >90% of patients (i.e., ~6 tons of unneeded clarithromycin/million treatments). In the late 1980s, the infectious disease community functionally transferred responsibility for the management of H. pylori to gastroenterology, which has managed the infection as another common gastrointestinal disease such as constipation. In 2022, both traditional and noninvasive molecular-based susceptibility testing for H. pylori became available in the United States. In order to reduce and prevent antibiotic misuse, the infectious disease community should reclaim responsibility for the management of this important infectious disease. Full article

Atrial fibrillation has been described as a global epidemic with a three-fold increase in prevalence in the last 50 years. As the prevalence of atrial fibrillation continues to grow, multiple landmark trials have been designed to determine the best method to treat atrial fibrillation. Initial trials have stated that rate control was not inferior to rhythm control, however, as the efficacy of rhythm control of atrial fibrillation has improved, a benefit in rhythm control has been shown. Because of this trend towards increased rhythm control, more patients have been placed on anti-arrhythmic medications. This paper will review the epidemiology and clinical impact of the utilization of anti-arrhythmic medications. As we enter the era of rhythm control, increased awareness is needed regarding the monitoring and potential adverse events that can occur with these medications. Providers must balance the increased emphasis on rhythm control with the overall clinical impact on their patients due to drug-to-drug interactions and adverse effects that can occur with different co-morbidities. If the clinical momentum towards rhythm control continues, real-world data analysis will be needed to evaluate the clinical impact of the use, risk, and benefits of anti-arrhythmic medications. Full article